Methods and kit for treating parkinson&#39;s disease

ABSTRACT

The efficacy of levodopa therapy in patients being treated for Parkinson&#39;s disease is enhanced by administering high doses of a partial glycine agonist. The frequency and severity of levodopa-induced side effects in Parkinson&#39;s disease patients are also reduced by administration of a partial glycine agonist.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of co-pending U.S. provisionalapplication Ser. No. 60/410,512, filed on Sep. 13, 2002, the entiredisclosure of which is herein incorporated by reference.

FIELD OF THE INVENTION

The invention relates to therapies for Parkinson's Disease (“PD”), andin particular to methods and a kit for enhancing the efficacy oflevodopa treatment and reducing levodopa-induced side effects with highdoses of a partial glycine agonist.

BACKGROUND OF THE INVENTION

Parkinson's disease is a progressive disorder of the central nervoussystem affecting over 1.5 million people in the United States.Parkinson's disease is caused by the degeneration of the pigmentedneurons in the substantia nigra of the brain, resulting in decreaseddopamine availability to the striatum. Clinically, the disease ischaracterized by a decrease in spontaneous movements, gait difficulty,postural instability, rigidity and tremor.

The most common and effective drug for treatment of PD is levodopa,either administered alone or in combination with a peripheral dopadecarboxylase inhibitor such as carbidopa. After about 5 years oftreatment, however, the majority of PD patients experience a“wearing-off” of drug effect, and often exhibit abnormal motor sideeffects (e.g., dyskinesias and dystonias) in response to the levodopa.These problems limit the long-term benefit that can be achieved withthis drug.

Currently, the dose of levodopa can be reduced somewhat by addingdopamine agonists such as bromocriptine mesylate (Parlodel), pergolidemesylate (Permax), pramipexole (Mirapex), or ropinirole hydrochloride(Requip), however, these drugs have no effect on the duration ofanti-parkinson efficacy of levodopa. Enzyme inhibitors such as acatechol-O-methyl transferase inhibitors (tolcapone or entacapone) ormonoamine oxidase B inhibitors (selegiline) may extend the duration oflevodopa's therapeutic effect. However, dopamine agonists and enzymeinhibitors directly manipulate dopamine neurochemistry. Side effectsrelated to excess dopaminergic neurotransmission, such as dyskinesiasand psychoses, are thus often produced when these drugs are used inconjunction with levodopa to treat PD. Also, neither the dopamineagonists nor the enzyme inhibitors have significant anti-Parkinsoneffects of their own.

Up to 80% of PD patients on levodopa therapy develop levodopa-induced,choreiform dyskinesias after 2-5 years of levodopa use. Whenlevodopa-induced dyskinesias first emerge, they are mainly the peak-dosetype; i.e., the dyskinesias are most prominent in PD patients whenplasma levodopa levels are high. After chronic levodopa treatment,dyskinesias can appear at the beginning and again at the end of theperiod during which an individual levodopa has a beneficial effect. Inmore advanced PD, dyskinesias can be present throughout the duration ofa single oral dose of levodopa, often masking any beneficial effects ofthe drug.

Functional models of levodopa-induced dyskinesias suggest that there isenhanced excitation in the striatum, which may be linked to thespontaneous release of glutamate after dopamine denervation. Drugs thatact directly to antagonize glutamate receptors would likely not beuseful in treating levodopa-induced dyskinesias, since there is littleevidence of gross alterations in the levels or synthesis of anyglutamate receptor subtype in parkinsonian brains. Thus, the abnormalglutamate-mediated influences that underlie levodopa-induced dyskinesiasare most likely caused by altered glutamate neurotransmission.

Drugs such as amantadine or riluzole have recently been proposed asanti-dyskinesia treatments to be used in conjunction with levodopa. Someof these drugs reduce the efficacy of levodopa while minimizingdyskinesias, but none have enhanced the therapeutic effect of levodopa.Moreover, amantadine as well as other drugs that indiscriminately blockglutamate receptors can cause confusion, hallucinations, depression,nightmares, and blurred vision, and the anti-dyskinetic effect wears offafter a few weeks of treatment.

Chronic levodopa therapy can also cause other sides effects such asdystonias (e.g., sustained muscle contractions resulting in abnormalpostures). The type and pattern of levodopa side effects can differ frompatient to patient. It is not known why levodopa causes different sideeffects in different patients; however, dystonias and dyskinesias arebelieved to be caused by dysfunctions in different neural systems.

The emergence of levodopa-induced side effects presents a dilemma forthe management of PD patients. For example, a decrease in the levodopadose may relieve the side effects, but is achieved at the expense ofincreasing PD symptoms. In pharmacological terms, the therapeutic indexof levodopa lessens over time, because the incidence of toxicside-effects increases for a given levodopa dose over the course oftreatment.

Altered N-methyl D-aspartate (“NMDA”) receptor transmission may also beinvolved in abnormal neural activity in basal ganglia circuits followingdopamine depletion in PD patients. Receptor binding studies have shownthat NMDA receptors in dopamine-depleted striata have increased neuron“activatability” in the presence of glutamate and glycine. Also, theanimal experimental literature reports that antagonists of excitatoryNMDA receptors may exert anti-parkinsonian effects.

However, the clinical usefulness of specific NMDA antagonists intreating PD is limited, because such drugs produce severe, debilitatingside effects. Likewise, although drugs that block specific NMDA receptorsubtypes may have some anti-parkinson properties and may reducedyskinesias, it is unclear which NMDA subtypes need to be blocked toeffectively treat PD.

Drugs that can simultaneously act as both agonists and antagonists andare called “partial agonists.” The agonist or antagonist properties ofsuch drugs are often dependent on their concentration within the brainrelative to endogenous neurotransmitter levels. In parts of the brainwhere endogenous neurotransmitter levels are relatively low, a partialagonist can increase receptor stimulation. In regions whereneurotransmitter levels are relatively high, partial agonists can act asantagonists and reduce receptor stimulation.

Glycine is a coagonist of the NMDA receptor with respect to activationof both the glutamate and glycine sites required for channel opening.Drugs like D-cycloserine or 1-aminocyclopropanecarboxylic acid (ACPC)are partial agonists for the glycine binding site of the NMDA receptor.These drugs, also called “partial glycine agonists,” can act as agonistsor antagonists at the NMDA receptor glycine binding site, depending ontheir concentration in the brain relative to endogenous glycine.Generally, partial glycine agonists act as antagonists at highconcentrations in the brain relative to glycine, without directlyblocking the NMDA receptor.

The partial glycine agonists have no affinity for neurotransmitteruptake sites, and, unlike NMDA channel blockers, do not produce motorincoordination or ataxia. Thus, partial glycine agonists acting asantagonists have a safer side effect profile compared to drugs that actdirectly on NMDA, adrenergic, histaminergic, cholinergic orglutamatergic receptors.

There is a need for a drug which increases the therapeutic efficacy oflevodopa in PD patients without producing toxic side-effects related toexcess dopamine neurotransmission, or the direct inhibition of NMDA andother neuroreceptors. Ideally, the treatment would also reduce theseverity and frequency of levodopa-induced dyskinesias in PD patientsduring the course of levodopa therapy.

SUMMARY OF THE INVENTION

It has now been found that the therapeutic efficacy of levodopa intreating PD is improved when administered with high doses of a partialglycine agonist. The frequency and severity of levodopa-induced motorside-effects, such as dyskinesias and dystonias, are also reduced whenlevodopa is administered with a high dose of a partial glycine agonist.

The invention therefore provides a method for treating Parkinson'sdisease in a subject in need of such treatment, comprising administeringlevodopa and a high dose of a partial glycine agonist to the subject,wherein the efficacy of the levodopa is enhanced or the frequency andseverity of levodopa-induced side effects in the subject is reduced.

The invention also provides a method for increasing the therapeuticindex of levodopa in a subject being treated for Parkinson's disease,comprising administering levodopa and a high dose of a partial glycineagonist to the subject.

The invention also provides a method of treating PD in a subject in needof such treatment, comprising administering a high dose of a partialglycine agonist to the subject.

The invention further provides kit comprising a partial glycine agonistand instructions for administering the partial glycine agonist at a highdose, either alone or in combination with levodopa, for the treatment ofParkinson's disease.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a histogram showing enhanced duration of the levodopaanti-Parkinson effect upon administration of D-cycloserine (“DCS”) andlevodopa/benserazide (“L-Dopa”), as compared to t-Dopa alone.

FIG. 2 is a histogram showing the inhibition of dyskinesias uponadministration of D-cycloserine (“DCS”) and levodopa/benserazide(“L-Dopa”), as compared to L-Dopa alone. Data are expressed as the mean(avg.) dyskinesia scores±SD.

FIG. 3 is a histogram showing the inhibition of dystonia uponadministration of D-cycloserine (“DCS”) and levodopa/benserazide(“L-Dopa”), as compared to L-Dopa alone. Data are presented as the mean(avg.) dystonia scores±SD.

FIG. 4 is a histogram showing that administration of D-cycloserine(“DCS”) with levodopa/benserazide (“L-Dopa”) did not interfere with orreduce the symptomatic efficacy of L-Dopa when assessed thirty (“L-Dopa(30)”) or sixty (“L-Dopa (60)”) minutes after levodopa administration.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that administering a high dose of a partialglycine agonist to subjects undergoing levodopa therapy and levodopaenhances the duration of effect of levodopa (i.e., prevents the “wearingoff” phenomenon), provides a greater therapeutic effect than levodopaalone, and decreases the severity and frequency of side effects thatresult from long-term use of levodopa. Treatment of PD patients with ahigh dose of a partial glycine agonist and levodopa also allows for adecrease in levodopa dosage, which helps delay the wearing-off effectand the onset of levodopa-induced side effects.

Partial glycine agonists acting as antagonists also decrease neuronalexcitotoxicity caused by excessive glutamate neurotransmission in theparkinsonian brain. Decreasing neuronal excitotoxicity hasantidepressant and anxiolytic effects, and can also have a positiveeffect on certain types of cognitive disorders. Depression and anxietyare common complications in subjects with PD. Thus, treatment of thesecomplications is an added advantage to the administration of a partialglycine agonist with levodopa.

A subject suffering from PD can therefore be treated with levodopa and ahigh dose of a partial glycine agonist. Partial glycine agonists areknown to those skilled in the art, and include D-cycloserine, D-serine,and 1-aminocyclopropanecarboxylic acid (ACPC). As used herein, a partialglycine agonist also includes substances which convert other substancesinto a partial glycine agonist in the body (e.g., serine racemase, whichconverts L-serine to D-serine). A preferred partial glycine agonist isD-cycloserine.

As used herein, a “high dose” of a partial glycine agonist is a dosewhich produces a partial glycine agonist concentration in the brain of asubject at which the partial glycine agonist antagonizes the glycinebinding site of the NMDA receptor. Preferably, a high dose of a partialglycine agonist is greater than 1 mg/kg body weight of the subject to betreated, for example at least 2 mg/kg, at least 3 mg/kg, at least 4mg/kg, at least 5 mg/kg, at least 6 mg/kg, at least 7 mg/kg or at least8 mg/kg partial glycine agonist. Preferably, at least 8 mg/kg partialglycine agonist is administered to the subject, for example 8 to 12mg/kg partial glycine agonist.

As used herein, a “subject” is any mammal suffering from PD orexhibiting symptoms of PD. A subject can be a primate (e.g., human ormacaque) or a rodent (e.g., mouse, rat or guinea pig), but is preferablya human. One skilled in the art can readily determine if a subject issuffering from PD or exhibiting PD symptoms by performing a standardclinical or neurological assessment; for example, by using the UnifiedParkinson's Disease Rating Scale (UPDRS).

As used herein, “Parkinson's disease” or “PD” includes PD of anyetiology, including idiopathic PD, postencephalitic PD, PD resultingfrom chronic manganese poisoning or carbon monoxide poisoning,parkinsonism-dementia of Guam and hemiparkisonism. PD also includes anyneurological syndrome of undetermined etiology which a subject presentswith neurological symptoms associated with a decrease in dopamineproduction or dopaminergic transmission in the brain.

The high dose partial glycine agonist can be administered to the subjectby any enteral or parenteral route. Enteral administration is preferred.

Suitable enteral administration routes include oral or rectal. Apreferred enteral administration route is oral. Suitable parenteraladministration routes include intravascular administration (e.g.intravenous bolus injection, intravenous infusion, intra-arterial bolusinjection, intra-arterial infusion and catheter instillation into thevasculature); subcutaneous injection or deposition includingsubcutaneous infusion (such as by osmotic pumps); intramuscularinjection, intraperitoneal injection, transdermal, nasal orinhalational.

The levodopa and partial glycine agonist can be administered to asubject together or separately. For example, the levodopa and partialglycine agonist can be administered simultaneously by the same route, orcan be administered by different routes or at different times.Preferably, the partial glycine agonist and levodopa are administered tothe subject no more than twelve hours apart, for example no more thaneight hours apart or no more than four hours apart. When the partialglycine agonist and levodopa are not administered simultaneously, theorder in which the partial glycine agonist and levodopa are administeredto the subject is not critical. In a particularly preferred embodiment,the partial glycine agonist and levodopa are administered to a subjectat approximately the same time and by the same route.

One skilled in the art can readily determine the amount of levodopa tobe administered to a subject along with high dose partial glycineagonist. In general, a subject being treated for PD receives an initiallevodopa dose of 100 mg to 1 g daily, usually in 250 mg increments fourtimes a day. The levodopa dose can be increased in increments of 100 to750 mg/day at 3 to 7 day intervals, until a daily maintenance dose of2.5 to 6 g/day is reached. Generally, no more than 8 g/day levodopashould be administered.

In the practice of the present method, the levodopa and partial glycineagonist can optionally be administered with a peripheral dopadecarboxylase inhibitor, such as carbidopa or benserazide. One skilledin the art can readily determine the amount of peripheral dopadecarboxylase inhibitor to be administered to a subject. In general, 10mg of carbidopa or 15 mg of benserazide can be given 2-3 times dailywith levodopa to the average adult human. Carbidopa or benserazidedosage can be adjusted upward daily until the desired effect is seen.Combined carbidopa/levodopa formulations are available commercially, forexample, from Bristol Meyers Squibb Co., Princeton, N.J., as Sinemet®.

Administering a high dose of partial glycine agonist increases theefficacy of a given levodopa dose in a subject being treated for PD. Asused herein, “increasing the efficacy of levodopa” refers to increasingthe duration of the effect of levodopa for a given dose. The duration ofeffect of a levodopa dose can be measured by monitoring one or moresymptoms of PD in a subject undergoing levodopa therapy with a partialglycine agonist, and comparing that to the length of time the symptomsare alleviated in a subject undergoing levodopa therapy without highdose partial glycine agonist. Alternatively, the length of time that thePD symptoms are alleviated in a subject receiving levodopa and a partialglycine agonist can be compared to the length of time that the symptomswere alleviated in same subject prior to receiving high dose partialglycine agonist.

Increasing the duration of effect of a levodopa dose with high dosepartial glycine agonist allows one to give fewer levodopa doses, or toreduce the levodopa standard dose, but still achieve the sametherapeutic effect. This is particularly advantageous, because givingfewer or reduced levodopa doses to a subject with PD delays the point atwhich levodopa becomes ineffective.

Administering a high dose of partial glycine agonist also reduces thefrequency or severity of levodopa-induced side effects, such asdyskinesias and dystonias.

One skilled in the art can readily determine whether the frequency orseverity of levodopa-induced dyskinesias is reduced by using anysuitable technique for the clinical assessment of involuntary movementsin subjects with PD. For example, the frequency and severity oflevodopa-induced dyskinesias can be assessed using the AbnormalInvoluntary Movement Scale (AIMS).

For example, assessment of subjects undergoing levodopa therapy withhigh dose partial glycine agonist are subjected to a six-week AIMStrial. During the AIMS trial, subjects fill out a detailed diary whichto the severity of any dyskinesias and assess daily function accordingto the following scales:

Dyskinesia Intensity: 0—without dyskinesia; 1—mild dyskinesia; 2—mediumdyskinesia; 3—severe dyskinesia.

Rating of Daily Function: 1—improvement of daily function as compared tothe basic condition; 2—no improvement in daily function; 3—deteriorationof daily function as compared to the basic condition.

A reduction in the daily AIMS scores during the course of the trialindicates that the frequency and severity of dyskinesias in beingreduced. Alternatively, AIMS scores obtained after administration oflevodopa and high dose partial glycine agonist to a subject can becompared to AIMS (or similar test) scores obtained for the subject priorto treatment with high dose partial glycine agonist.

One skilled in the art can also readily determine whether the frequencyor severity of levodopa-induced dystonias is reduced by using anysuitable technique for the clinical assessment of involuntary, sustainedmuscle contraction in subjects with PD. For example, frequency orseverity of dystonias can be determined by clinical observation of thesubject, including reflex studies, or by techniques such aselectromyography (EMG) or nerve conduction velocity tests.

The invention also provides a method for increasing the therapeuticindex of levodopa in a subject being treated for Parkinson's disease,comprising administering levodopa and a high dose of a partial glycineagonist to the subject.

As used herein, “therapeutic index” refers to a quantitative measure ofthe selectivity of a drug when a therapeutic effect (“E”) and a toxiceffect (“T”) are being compared. The therapeutic index can then becalculated as ED₅₀/TD₅₀, at some arbitrary level of response observed ina subject receiving the drug. The ED₅₀ is the dose required to generatethe desired intensity of therapeutic effect in 50% of the subjectstested. The TD₅₀ is the dose required to generate the toxic effect in50% of the subjects tested.

The therapeutic index is a useful indicator of the benefit versusadverse effect of a drug. Those drugs which have a high therapeuticindex can be administered over a wide range of effective doses withoutincurring significant adverse events. Conversely, drugs having a smalltherapeutic index can be administered over a small range of effectivedoses without incurring significant adverse events. The therapeuticindex of levodopa lessens over time with chronic administration.

As discussed above, high doses of partial glycine agonist increase theefficacy of levodopa while also reducing toxic side effects. Thus, thetherapeutic index of levodopa is increased by administration of a highdose partial glycine agonist. As discussed above, techniques fordetermining whether the efficacy of levodopa has increased, and whethertoxic side effects of levodopa have been reduced, are within the skillin the art. Suitable doses of the partial glycine agonist and suitableroutes of administration are as described above.

Substances which inhibit peripheral dopa decarboxylase (e.g., carbidopaor benserazide) can also be administered to subject with levodopa and apartial glycine agonist in order to increase the therapeutic index oflevodopa.

In another embodiment, the invention provides a method of treating PD ina subject, comprising administering to a subject in need of suchtreatment a partial glycine agonist. Without wishing to be bound by anytheory, it is believed that altered NMDA receptor transmission may beinvolved in abnormal basal ganglia activity in PD. Partial glycineagonists acting as non-selective antagonists of the NMDA receptor cancorrect this altered NMDA receptor transmission. Suitable doses of thepartial glycine agonist and suitable routes of administration are asdescribed above. Substances which inhibit peripheral dopa decarboxylase(e.g., carbidopa or benserazide) can also be administered to subjectwith levodopa and a partial glycine agonist.

The invention also provides a kit comprising a partial glycine agonistand instructions for administering a high dose of the partial glycineagonist to a subject suffering from PD. The instructions can specifythat the partial glycine agonist is administered with or withoutlevodopa. Preferably, the instructions specify that the partial glycineagonist is administered with levodopa. The instructions can also specifythat the partial glycine agonist can be administered with a peripheraldopa decarboxylase inhibitor such as carbidopa or benserazide.

In one embodiment, the kit further comprises levodopa. In anotherembodiment, the kit further comprises levodopa and a peripheral dopadecarboxylase inhibitor. Preferably, the kit comprises a partial glycineagonist and levodopa in a single-dose pharmaceutical composition, inwhich the amount of partial glycine agonist is sufficient to delivergreater than 1 mg/kg body weight of the subject to be treated. Forexample, the single-dose pharmaceutical composition can deliver at least2 mg/kg, at least 3 mg/kg, at least 4 mg/kg, at least 5 mg/kg, at least6 mg/kg, at least 7 mg/kg or at least 8 mg/kg, for example 8 to 12mg/kg, partial glycine agonist to the subject.

One skilled in the art can readily prepare pharmaceutical compositionscomprising a partial glycine agonist, or comprising a partial glycineagonist and levodopa, for example by using the principles set forth inRemington's Pharmaceutical Science, 18^(th) edit. (Alphonso Gennaro,ed.), Mack Publishing Co., Easton, Pa., 1990. Preferred pharmaceuticalcompositions of the invention comprise a partial glycine agonist,levodopa and a peripheral dopa decarboxylase inhibitor such as carbidopaor benserazide.

In one embodiment, the invention provides a single-dose pharmaceuticalcomposition comprising a partial glycine agonist and levodopa. As usedherein, a “single-dose pharmaceutical composition” is a pharmaceuticalcomposition in which the partial glycine agonist and levodopa areprovided together in the same formulation, and in which the amount ofpartial glycine agonist is sufficient to deliver greater than 1 mg/kgbody weight of the subject to be treated.

The pharmaceutical compositions of the invention can be in a formsuitable for oral use, for example, as tablets, aqueous or oilysuspensions, dispersible powders or granules, emulsions, hard or softcapsules, or syrups or elixirs. Pharmaceutical compositions of theinvention intended for oral use can be prepared according to anytechnique suitable for the manufacture of oral pharmaceuticalcompositions, for example as disclosed in U.S. Pat. Nos. 4,190,672;6,376,545; and 6,365,180, the entire disclosures of which are hereinincorporated by reference.

Oral pharmaceutical compositions of the invention can contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents, and preserving agents in order toprovide a pharmaceutically elegant and palatable preparation.

Pharmaceutical compositions of the invention comprising tablets cancontain a partial glycine agonist optionally with levodopa or levodopaand a peripheral dopa decarboxylase inhibitor, in admixture withnon-toxic pharmaceutically acceptable excipients which are suitable formanufacture of tablets. Suitable excipients include inert diluents, forexample calcium carbonate, sodium carbonate, lactose, calcium phosphate,or sodium phosphate; granulating and disintegrating agents, for examplemaize starch, or alginic acid; binding agents, for example starch,gelatin, or acacia; and lubricating agents, for example magnesiumstearate, stearic acids, or talc. The tablets can be uncoated or theycan be coated by known techniques to delay disintegration and adsorptionin the gastrointestinal tract, and thereby provide a sustained actionover a longer period.

Pharmaceutical compositions of the invention can also comprise hardgelatin capsules, wherein the partial glycine agonist, optionally withlevodopa or levodopa and a peripheral dopa decarboxylase inhibitor, ismixed with an inert solid diluent; for example calcium carbonate,calcium phosphate, or kaolin. Pharmaceutical compositions of theinvention can also comprise soft gelatin capsules, wherein the partialglycine agonist, optionally with levodopa or levodopa and a peripheraldopa decarboxylase inhibitor, is mixed with an oil medium; e.g., archisoil, liquid paraffin, or olive oil.

Pharmaceutical compositions of the invention can also comprise liquidformulations comprising a partial glycine agonist, optionally withlevodopa or levodopa and a peripheral dopa decarboxylase inhibitor, inadmixture with excipients suitable for the manufacture of liquidformulations. In addition to water or saline, suitable excipients forliquid formulations include suspending agents such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia;dispersing or wetting agents such as lecithin, condensation products ofan alkylene oxide with fatty acids (e.g., polyoxethylene stearate),condensation products of ethylene oxide with long chain aliphaticalcohols (e.g., heptadecethyleneoxy-cetanol), condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol (e.g., polyoxyethylene sorbitol monooleate), or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate).

Liquid formulations according to the invention can also contain one ormore preservatives such as ethyl, n-propyl, or p-hydroxy benzoate; oneor more coloring agents; one or more flavoring agents; or one or moresweetening agents such as sucrose, saccharin, or sodium or calciumcyclamate.

Liquid formulations according to the invention can also containantioxidants, such as tocopherol, sodium metabisulphite, butylatedhydroxytoluene (BHT), butylated hydroxyanisole (BRA), ascorbic acid orsodium ascorbate.

Liquid formulations according to the invention can also be formulatedinto syrups or elixirs by admixing with sweetening/thickening agentssuch as glycerol, sorbitol or sucrose. Syrups or elixirs can alsocontain a demulcent, preservative, flavoring or coloring agent.

The pharmaceutical compositions of the invention can also be in the formof a sterile, pyrogen-free preparation suitable for parenteraladministration, for example as a sterile injectable aqueous suspension.This suspension can be formulated using the dispersing or wetting agentsand suspending agents described above. A sterile injectable preparationaccording to the invention can also comprise a sterile injectablesolution or suspension in a non-toxic, parenterally-acceptable diluentor solvent, for example, as a solution in 1,3-butane diol, water orsaline solution. Formulation of sterile, pyrogen-free pharmaceuticalcompositions suitable for parenteral administration are within the skillin the art, for example as described in U.S. Pat. No. 4,190,672, supra.

The invention will now be illustrated with the following non-limitingexamples.

EXAMPLE 1 Enhanced Duration of Anti-Parkinson Effect by Combination ofD-cycloserine and Levodopa

Eight mg/kg D-cycloserine was administered to two parkinsonian monkeyswith an established therapeutic response to levodopa, together with 40mg/kg levodopa plus the 15 mg of the peripheral dopa decarboxylaseinhibitor benserazide. Symptomatic benefit was assessed by raters blindto treatment condition. As shown in FIG. 1, administration of partialglycine agonist with levodopa enhanced the levodopa “on” time, orduration of symptomatic relief by levodopa, by 41% compared to levodopaplus benserazide alone.

EXAMPLE 2 Administration of Partial Glycine Agonist D-Cycloserine withLevodopa Reduces the Severity of Levodopa-Induced Dyskinesias

A parkinsonian monkey was primed for choreiform dyskinesia followingchronic administration of levodopa plus the peripheral dopadecarboxylase inhibitor benserazide. In this monkey, a 40 mg/kgchallenge dose of levodopa caused significant choreiform dyskinesias(see FIG. 2; “L-Dopa Avg.” bars). Eight mg/kg D-cycloserine administeredwith 40 mg/kg levodopa plus the 15 mg of the peripheral dopadecarboxylase inhibitor benserazide significantly decreased the severityof these dyskinesias at least over a period of 120 minutes (see FIG. 2;“L-Dopa+DCS Avg.” bars). Severity of the dyskinesias was rated byobservers blind to the treatment condition. Three independentrepetitions of the study were performed.

EXAMPLE 3 Addition of Partial Glycine Agonist D-Cycloserine to LevodopaTherapy Reduces the Severity of Levodopa-Induced Dystonias

In a parkinsonian monkey, chronic administration of levodopa plus theperipheral dopa decarboxylase inhibitor benserazide resulted inprimarily dystonia. Under these conditions, 8 mg/kg D-cycloserine wasadministered to the monkeys with 40 mg/kg levodopa plus 15 mgbenserazide. The severity of the dystonia was rated by observers blindto the treatment condition. As can be seen in FIG. 3, administration ofD-cycloserine (“DCS”) with levodopa/benserazide (“L-Dopa”) significantlydecreased the severity of the dystonias at least over a period of 120minutes. Three independent repetitions of the study were performed.

EXAMPLE 4 Addition of Partial Glycine Agonist D-Cycloserine to LevodopaTherapy Does Not Interfere with or Reduce the Anti-Parkinsonian Efficacyof Levodopa

In two parkinsonian monkeys with an established therapeutic response tolevodopa, peak-dose levodopa efficacy was assessed by raters blind totreatment condition. Eight mg/kg D-cycloserine was administered to themonkeys with 40 mg/kg levodopa plus 15 mg benserazide. As can be seen inFIG. 4, administration of the partial glycine agonist did not interferewith or reduce the therapeutic efficacy of levodopa (i.e., the abilityof the levodopa to relieve symptoms of parkinsonism).

The data shown in the figures and discussed in the above Examplesindicates that high doses of a partial glycine agonist are an effectiveanti-dyskinesia and anti-dystonia agent. Administration of high doses ofa partial glycine agonist also counteracts the significant “wearing off”problem experienced by many patients that use levodopa, by extending theduration of effect of a levodopa dose. Furthermore, high doses ofpartial glycine agonist do not reduce or interfere with the therapeuticeffect of levodopa.

All documents referred to herein are incorporated by reference. Whilethe present invention has been described in connection with thepreferred embodiments and the various figures, it is to be understoodthat other similar embodiments may be used or modifications andadditions made to the described embodiments for performing the samefunction of the present invention without deviating therefrom.Therefore, the present invention should not be limited to any singleembodiment, but rather should be construed in breadth and scope inaccordance with the recitation of the appended claims.

1-42. (canceled)
 43. A therapeutic combination comprising levodopa in an amount effective to treat Parkinson's disease in a subject, and a partial glycine agonist in an amount effective to enhance efficacy of the levodopa or to reduce frequency or severity of side effects of the levodopa in the subject.
 44. The combination of claim 43, further comprising a peripheral dopa decarboxylase inhibitor.
 45. The combination of claim 44, wherein the peripheral dopa decarboxylase inhibitor comprises carbidopa or benserazide.
 46. The combination of claim 43, wherein the partial glycine agonist comprises D-cycloserine or 1-aminocyclopropanecarboxylic acid.
 47. The combination of claim 43, wherein the amount of the partial glycine agonist is an amount per dose sufficient to deliver greater than 1 mg of partial glycine agonist per kg body weight of the subject.
 48. The combination of claim 43, wherein the partial glycine agonist is D-cycloserine and is present in an amount per dose sufficient to deliver greater than 1 mg to 12 mg of D-cycloserine per kg body weight of the subject.
 49. The combination of claim 43, wherein the amount of the partial glycine agonist is sufficient to produce a concentration thereof in the brain of the subject at which antagonism of the glycine binding site of the NMDA receptor occurs.
 50. The combination of claim 43, wherein the levodopa and glycine partial agonist are present in a single pharmaceutical composition.
 51. The combination of claim 50, wherein the single composition further comprises a peripheral dopa decarboxylase inhibitor.
 52. The combination of claim 43, wherein the levodopa and partial glycine agonist are present in separate pharmaceutical compositions.
 53. The combination of claim 43, wherein at least one of the levodopa and the partial glycine agonist is present in a form adapted for parenteral administration.
 54. The combination of claim 43, wherein at least one of the levodopa and glycine partial agonist is present in a form adapted for enteral administration.
 55. The combination of claim 54, wherein the levodopa and the glycine partial agonist are each present in a form adapted for oral administration.
 56. A pharmaceutical composition comprising (a) levodopa in an amount effective to treat Parkinson's disease in a subject, (b) a partial glycine agonist in an amount effective to enhance efficacy of the levodopa or to reduce frequency or severity of side effects of the levodopa in the subject, and (c) one or more pharmaceutically acceptable excipients.
 57. The composition of claim 56, further comprising a peripheral dopa decaboxylase inhibitor.
 58. The composition of claim 57, wherein the peripheral dopa decarboxylase inhibitor comprises carbidopa or benserazide.
 59. The composition of claim 56, wherein the partial glycine agonist comprises D-cycloserine or 1-aminocyclopropanecarboxylic acid.
 60. The composition of claim 56, wherein the amount of the partial glycine agonist is sufficient to deliver, per dose, greater than 1 mg of partial glycine agonist per kg body weight of the subject.
 61. The composition of claim 56, wherein the partial glycine agonist is D-cycloserine and is present in an amount sufficient to deliver, per dose, greater than 1 mg to 12 mg of D-cycloserine per kg body weight of the subject.
 62. The composition of claim 56, wherein the amount of the partial glycine agonist is sufficient to produce a concentration thereof in the brain of the subject at which antagonism of the glycine binding site of the NMDA receptor occurs.
 63. The composition of claim 56, that is in a form adapted for parenteral administration.
 64. The composition of claim 56, that is in a form adapted for enteral administration.
 65. The composition of claim 64, that is in a form adapted for oral administration.
 66. The composition of claim 56, that is in a form selected from the group consisting of aqueous and oily suspensions, tablets, dispersible powders and granules, emulsions, hard and soft capsules, syrups, elixirs, suppositories, liposome preparations, microencapsulated preparations, transdermal patches and sprays.
 67. The composition of claim 56, wherein the one or more excipients comprise at least one excipient selected from the group consisting of water, saline, suspending agents, dispersing agents, sweetening agents, flavoring agents, coloring agents, preserving agents, wetting agents, condensation agents, inert diluents, binding agents, lubricating agents, and combinations thereof.
 68. A method for treating Parkinson's disease in a subject, comprising administering levodopa and a partial glycine agonist to the subject, wherein the partial glycine agonist is administered in an amount effective to enhance efficacy of the levodopa or to reduce frequency or severity of side effects of the levodopa.
 69. The method of claim 68, further comprising administering a peripheral dopa decaboxylase inhibitor to the subject.
 70. The method of claim 69, wherein the peripheral dopa decarboxylase inhibitor comprises carbidopa or benserazide.
 71. The method of claim 68, wherein the partial glycine agonist comprises D-cycloserine or 1-aminocyclopropanecarboxylic acid.
 72. The method of claim 68, wherein the partial glycine agonist is administered in an amount per dose sufficient to deliver greater than 1 mg of partial glycine agonist per kg body weight of the subject.
 73. The method of claim 68, wherein the partial glycine agonist is D-cycloserine and is administered in an amount per dose sufficient to deliver greater than 1 mg to 12 mg of D-cycloserine per kg body weight of the subject.
 74. The method of claim 68, wherein the partial glycine agonist is administered in an amount sufficient to produce a concentration thereof in the brain of the subject at which antagonism of the glycine binding site of the NMDA receptor occurs.
 75. The method of claim 68, wherein the levodopa and the partial glycine agonist are administered in a single pharmaceutical composition.
 76. The method of claim 75, wherein the single composition further comprises a peripheral dopa decarboxylase inhibitor.
 77. The method of claim 68, wherein the levodopa and partial glycine agonist are administered in separate pharmaceutical compositions.
 78. The method of claim 68, wherein at least one of the levodopa and the partial glycine agonist is administered parenterally.
 79. The method of claim 68, wherein at least one of the levodopa and the partial glycine agonist is administered enterally.
 80. The method of claim 79, wherein the levodopa and the partial glycine agonist are each administered orally.
 81. The method of claim 68, wherein the frequency or severity is reduced of one or more levodopa side effects selected from the group consisting of dyskinesias, dystonias, deterioration of daily function, depression, anxiety, cognitive disorders and combinations thereof.
 82. The method of claim 68, wherein the subject is selected from the group consisting of primates and rodents.
 83. The method of claim 68, wherein the subject is human. 